APPRAISE-2: Apixaban risks outweigh benefits in high-risk ACS

Reed Miller

July 24, 2011

Kyoto, Japan - The full results of the APPRAISE-2 trial of the anticoagulant apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) in high-risk acute coronary syndrome (ACS) patients, which was stopped prematurely in November 2010, are now published online in the New England Journal of Medicine[1] . Lead investigator Dr John Alexander (Duke University, Durham, NC) presented the final results Monday morning here at the International Society on Thrombosis and Haemostasis Congress .

The idea of adding anticoagulants to antiplatelet therapy following acute coronary syndrome is just not a good idea.

APPRAISE-2 enrolled patients who were at high risk for recurrent ischemic events following acute coronary syndrome and on standard antiplatelet therapy. The trial randomized patients to either placebo or two 5-mg daily doses of apixaban, a direct factor Xa inhibitor. As reported by heartwire, the trial sponsors stopped the trial in November 2010 after recruiting 7392 patients because the interim data showed that the increase of major bleeding with apixaban was not counterbalanced by the hoped-for decrease in recurrent ischemic events.

Alexander told heart wire that the final results are consistent with the interim results that triggered the suspension of the trial in November. The increase in bleeding with apixaban was not a surprise, but the lack of a meaningful reduction in ischemic events was, Alexander said. "But it answers an important question. We've always thought that arterial thrombosis was platelet-mediated and coagulation-factor mediated, and this supports that hypothesis."

After a median follow-up of 241 days, 279 of 3705 patients randomized to apixaban experienced the primary end point of cardiovascular death, MI, or ischemic stroke (7.5%, or 13.2 events per 100 patient-years), compared with 293 of the 3687 of the patients randomized to placebo (7.9%, or 14 events per 100 patient-years). The hazard ratio with apixaban vs placebo was 0.95 (p=0.51).

There were more intracranial and fatal bleeding events in the apixaban group than the placebo group, and 46 of the apixaban patients (1.3% or 2.4 events per 100 patient-years) and 18 of the placebo patients suffered major bleeding (0.5%, or 0.9 events per 100 patient-years), the primary safety outcome of the study. The hazard ratio for major bleeding with apixaban vs placebo was 2.59 (p=0.001).

The decrease in ischemic events was offset by an increase in bleeding events in all predefined subsets in the study, including patients taking only aspirin or patients on aspirin plus clopidogrel; patients who had undergone invasive revascularization had similar results to those who had not.

Will anticoagulants on top of antiplatelets ever work?

"It's possible that in different populations and with different doses of anticoagulants that one might get a different result, but that still needs to be proven," Alexander said.

For example, the ongoing ATLAS-2 is comparing two different doses of rivaroxaban with placebo in acute coronary syndrome on low-dose aspirin therapy with or without a thienopyridine. "Maybe those results will be different, but at this point I think the idea of adding anticoagulants to antiplatelet therapy following acute coronary syndrome is just not a good idea in your run-of-the-mill post-ACS patients," he said.

If ATLAS-2 finds a dose of rivaroxaban that reduces ischemic events without a corresponding increase in bleeding, it's possible that apixaban might be similarly effective with a different dose or in a lower-risk population. "If they see a different pattern of results, then maybe there is a way forward to adding anticoagulants to antiplatelet therapy," he said. However, Alexander doubts ATLAS-2 will show that.

The benefits and risks of adding an anticoagulant to an antiplatelet regimen could change as more is learned about new antiplatelet agents such as prasugrel and ticagrelor , he said. He also pointed out that anticoagulants may provide more benefit to acute coronary syndrome patients who have "a stronger indication" for anticoagulants, such as those with atrial fibrillation and/or a prosthetic valve. "Those are patients where we pretty much have no idea what to do. We expect more bleeding in those patients with triple therapy, with anticoagulants plus antiplatelet therapy, but maybe they would have better efficacy. That's unknown at this point."

Dr David Garcia (University of New Mexico, Albuquerque) told heart wire that the APPRAISE-2 "results highlight the importance of balancing risks and benefits when using antithrombotic therapy. It is possible that a single antiplatelet agent—eg, aspirin—plus an anticoagulant would offer a better risk/benefit profile, but I am not certain that we can hope for thrombosis rates any lower than what we currently see with current therapy—ASA plus thienopyridine. If there is a patient subgroup for whom the risks of this 'triple therapy' are justified, I don't think we have found it yet." 

Apixaban has, however, proved its mettle in the setting of venous thromboembolism prevention following hip or knee replacement, as tested in the ADVANCE-2 and ADVANCE-3 clinical trials. It has been approved in Europe for this indication.

The company also recently released top-line results from the ARISTOTLE trial, saying that the drug is noninferior to warfarin in atrial-fibrillation patients for the prevention of stroke and systemic embolism. Full results from ARISTOTLE will be presented August 28, 2011 at the European Society of Cardiology 2011 Congress in Paris, France.

Alexander receives research support and consulting fees from Bristol-Myers Squibb and consulting honoraria from Pfizer. Disclosures for the co authors are available on the NEJM website.




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